Prostate cancer remains the most common form of cancer among all males in the US, with black men at highest risk (Jemal, A.; Siegel, R.; Ward, E.; Hao, Y.; Xu, J.; Thun, M. J., Cancer Statistics, 2009. CA Cancer J Clin 2009, caac.20006). It is also the second leading cause of cancer related deaths in the US among men, largely due to the progressively treatment resistant nature of the disease. Treatment options for early stage prostate cancer commonly involve various combinations of watchful waiting, radical prostatectomy, radiation therapy, and very importantly, androgen-deprivation therapy (ADT) (Georgi, P.; Ronald, L. H.; Joel, B. N., The Treatment of Prostate Cancer.&nbsp. Cancer Practice 2001, 9 (6), 295-306). Prostate cancer is dependent upon androgen hormone steroids such as dihydrotestosterone (DHT) for sustaining and promoting growth. They do this by binding to the Androgen Receptor (AR) and localizing to the nucleus where it forms a complex that up regulates the transcription of critical genes. ADT is accomplished by either (i) administering antagonist to the AR that blocks androgen ligands (such as DHT), or by (ii) castration, in order to reduce the amount of testosterone available. Often both methods of ADT are used. However, the disease frequently advances to the much more lethal castration-resistant prostate cancer (CRPC), becoming resistant to these therapies by overexpressing ARs (Chen, C. D.; Welsbie, D. S.; Tran, C.; Baek, S. H.; Chen, R.; Vessella, R.; Rosenfeld, M. G.; Sawyers, C. L., Molecular determinants of resistance to antiandrogen therapy. Nature Medicine 2004, 10 (1), 33-39; Papatsoris, A. G.; Karamouzis, M. V.; Papavassiliou, A. G., Novel biological agents for the treatment of hormone-refractory prostate cancer (HRPC). Current Medicinal Chemistry 2005, 12 (3), 277-296). The expression levels of AR is about six-fold higher in castration resistant as compared to hormone-sensitive prostate cancer (inj a, M. J.; Savinainen, K. J.; Saramaki, O. R.; Tammela, T. L. J.; Vessella, R. L.; Visakorpi, T., Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res. 2001, 61 (9), 3550-3555). The effective treatment options for patients at this point have been exhausted. Options currently available for CRPC are supportive care, salvage endocrine manipulations, radiotherapy, radioactive isotopes, bisphosphonates and chemotherapy (Lara, P. N.; Meyers, F. J., Treatment options in androgen-independent prostate cancer. Cancer Investigation 1999, 17 (2), 137-144). These options are not curative.
The understanding that AR overexpression is one of the major causes of hormone refractory prostate cancer, and the dependency of the growth of the hormone refractory prostate on the binding of AR ligands, suggest that AR is a viable target for this form of malignancy. The preference of anti-androgen as agents for prostate cancer therapy is predicated on the selectivity and fewer side effects of these agents. The discovery and the use thereof of these anti-androgens have been well documented in several patents such as U.S. Pat. No. 7,709,517, U.S. Pat. No. 4,097,578, U.S. Pat. No. 5,411,981, U.S. Pat. No. 5,705,654, PCT International Applications WO 97/00071 and WO 00/17163, U.S. Published Patent Application No. 2004/0009969, U.S. Published Patent Application No. 2007/0004753, U.S. Published Patent Application No. 2008/0139634 and U.S. Published Patent Application No. 2010/0172975. However, the anti-androgens in common clinical use, such as bicalutamide (brand name: Casodex), have curative effects only on hormone sensitive prostate cancer and not on hormone refractory prostate cancer. The lack of the activity of most anti-androgens against refractory prostate cancer is partly due to their weak antagonist activities and strong agonist activities when AR is overexpressed as in refractory prostate cancer. The availability of AR inhibitors with more potent antagonistic activities and minimal agonistic activities has been described a viable approach to delay the progression and/or treat hormone refractory prostate cancer (U.S. Pat. No. 7,709,517, U.S. Published Patent Application No. 2007/0004753, U.S. Published Patent Application No. 2008/0139634 and U. S. Published Patent Application No. 2010/0172975). Alternatively, the current anti-androgens, including but not limiting to the more potent diarylhydantions described in U.S. Pat. No. 7,709,517, U.S. Published Patent Application No. 2007/0004753, U.S. Published Patent Application No. 2008/0139634 and U.S. Published Patent Application No. 2010/0172975, could be designed to incorporate a new cancer inhibiting moiety. Our molecular docking analysis revealed that prototypical simple HDAC inhibiting pharmacophores could ideally function as the new cancer inhibiting moiety (unpublished results).
The histone protein complex associates with DNA to form the higher order structure called chromatin. The histones are bound either loosely to form “beads on a string” that are accessible to transcriptional activity, or a tighter chromatin complex that reduces access to the genetic information. The genomic flux is regulated by the tightness of binding through modifications such as methylation, acetylation, or phosphorylation of the histones (Minucci, S.; Pelicci, P. G., Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer 2006, 6 (1), 38-51). Two families of proteins that are involved in controlling the extent of acetylation are histone acetyl transferases (HATs), which place an acetyl group onto the lysine of a histone protein, and histone deacetylases (HDACs), which remove it. There are 11 known isoforms of HDAC enzymes in Class I and II, which employ catalytic Zn2+ embedded in the active site. In many cancers, including prostate cancer, it has been observed that there is aberrant transcriptional silencing that is the result of HDAC enzymes being in unusually high abundance. The up regulation of HDAC activity has been connected with the down regulation of key onco-suppressor proteins (Martinez-Iglesias, O.; Ruiz-Llorente, L.; Sanchez-Martinez, R.; Garcia, L.; Zambrano, A.; Aranda, A., Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clin. Transl. Oncol. 2008, 10 (7), 395-398).
HDAC inhibition has been validated as a clinically viable cancer therapy in recent years. Suberoylanilide hydroxamic acid (SAHA,) received FDA approval for treatment of cutaneous T-cell lymphoma in 2006, along with FK228 which gained approval in 2009. Many other HDACi are being enthusiastically investigated, with several clinical trials running currently (Richon, V. M.; Emiliani, S.; Verdin, E.; Webb, Y.; Breslow, R.; Rifkind, R. A.; Marks, P. A., A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc. Natl. Acad. Sci. U.S.A. 1998, 95 (6), 3003-3007; Tan, J. H.; Cang, S. D.; Ma, Y. H.; Petrillo, R. L.; Liu, D. L., Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J. Hematol. Oncol. 2010, 3). One of the major drawbacks of present HDAC inhibitors is their lack of isoform, tissue, and cell type selectivity, resulting in toxicity and low potency. An approach that selectively target HDAC inhibitors to the diseased cells could ameliorate many of these drawbacks.
All HDAC inhibitors so far reported fit a three-motif pharmacophoric model namely, a zinc-binding group (ZBG), a hydrophobic linker and a recognition cap-group (Miller, T. A.; Witter, D. J.; Belvedere, S., J. Med. Chem., 46, 5097-5116 (2003)). We have observed a convergence of structure activity relationship (SAR) between the aryl recognition cap-group of HDAC inhibitors and diarylhydantoin anti-androgens that enabled the design of arylhydantoin derived HDAC inhibitors (unpublished results). These arylhydantoin derived HDAC inhibitors, through the interactions between AR and their anti-androgen moiety, are expected to target androgen positive prostate tumors and become selectively uptaken into and/or retained in the tumor cell. This approach should provide a highly desirable treatment options that become increasingly more selective and potent as the disease progresses from the hormone sensitive to the hormone refractory stage.
It is therefore an object of the invention to provide arylhydantoin derived HDAC inhibitors with improved selectivity for prostate malignacies and methods of making and using thereof.